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Principles For Enhancing Virus Capsid Capacity And Stability From A Thermophilic Virus Capsid Structure, Nicholas P. Stone, Gabriel Demo, Emily Agnello, Brian A. Kelch 2019 University of Massachusetts Medical School

Principles For Enhancing Virus Capsid Capacity And Stability From A Thermophilic Virus Capsid Structure, Nicholas P. Stone, Gabriel Demo, Emily Agnello, Brian A. Kelch

University of Massachusetts Medical School Faculty Publications

The capsids of double-stranded DNA viruses protect the viral genome from the harsh extracellular environment, while maintaining stability against the high internal pressure of packaged DNA. To elucidate how capsids maintain stability in an extreme environment, we used cryoelectron microscopy to determine the capsid structure of the thermostable phage P74-26. We find the P74-26 capsid exhibits an overall architecture that is very similar to those of other tailed bacteriophages, allowing us to directly compare structures to derive the structural basis for enhanced stability. Our structure reveals lasso-like interactions that appear to function like catch bonds. This architecture allows the capsid ...


Debrowser: Interactive Differential Expression Analysis And Visualization Tool For Count Data, Alper Kucukural, Onur Yukselen, Deniz M. Ozata, Melissa J. Moore, Manuel Garber 2019 University of Massachusetts Medical School

Debrowser: Interactive Differential Expression Analysis And Visualization Tool For Count Data, Alper Kucukural, Onur Yukselen, Deniz M. Ozata, Melissa J. Moore, Manuel Garber

Program in Bioinformatics and Integrative Biology Publications and Presentations

BACKGROUND: Sequencing data has become a standard measure of diverse cellular activities. For example, gene expression is accurately measured by RNA sequencing (RNA-Seq) libraries, protein-DNA interactions are captured by chromatin immunoprecipitation sequencing (ChIP-Seq), protein-RNA interactions by crosslinking immunoprecipitation sequencing (CLIP-Seq) or RNA immunoprecipitation (RIP-Seq) sequencing, DNA accessibility by assay for transposase-accessible chromatin (ATAC-Seq), DNase or MNase sequencing libraries. The processing of these sequencing techniques involves library-specific approaches. However, in all cases, once the sequencing libraries are processed, the result is a count table specifying the estimated number of reads originating from each genomic locus. Differential analysis to determine which loci ...


Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling And Increases Survival In Cancer Cachexia Syndrome, Felipe Henriques, Magno A. Lopes, Felipe O. Franco, Pamela Knobl, Kaltinaitis B. Santos, Luana L. Bueno, Victor A. Correa, Alexander H. Bedard, Adilson L. Guilherme, Alexander Birbrair, Sidney B. Peres, Stephen R. Farmer, Miguel L. Batista Jr. 2018 University of Massachusetts Medical School

Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling And Increases Survival In Cancer Cachexia Syndrome, Felipe Henriques, Magno A. Lopes, Felipe O. Franco, Pamela Knobl, Kaltinaitis B. Santos, Luana L. Bueno, Victor A. Correa, Alexander H. Bedard, Adilson L. Guilherme, Alexander Birbrair, Sidney B. Peres, Stephen R. Farmer, Miguel L. Batista Jr.

Open Access Articles

Cancer-induced cachexia, characterized by systemic inflammation, body weight loss, adipose tissue (AT) remodeling and muscle wasting, is a malignant metabolic syndrome with undefined etiology. Here, we show that both genetic ablation and pharmacological inhibition of TLR4 were able to attenuate the main clinical markers of cachexia in mice bearing Lewis lung carcinoma (LLC). AT remodelling was not found in LLC tumor-bearing (TB) TLR4(-/-) mice due to reduced macrophage infiltration and adipocyte atrophy. TLR4(-/-) mice were also resistant to cold-induced browning of subcutaneous AT (scAT). Importantly, pharmacological inhibition of TLR4 (Atorvastatin) reproduced the main protective effect against AT remodeling found in ...


The Trim-Nhl Protein Nhl-2 Is A Co-Factor In The Nuclear And Somatic Rnai Pathways In C. Elegans, Gregory M. Davis, Shikui Tu, Jacqueline A. Wilce, Julie M. Claycomb, Zhiping Weng, Peter R. Boag 2018 Federation University

The Trim-Nhl Protein Nhl-2 Is A Co-Factor In The Nuclear And Somatic Rnai Pathways In C. Elegans, Gregory M. Davis, Shikui Tu, Jacqueline A. Wilce, Julie M. Claycomb, Zhiping Weng, Peter R. Boag

Program in Bioinformatics and Integrative Biology Publications and Presentations

Proper regulation of germline gene expression is essential for fertility and maintaining species integrity. In the C. elegans germline, a diverse repertoire of regulatory pathways promote the expression of endogenous germline genes and limit the expression of deleterious transcripts to maintain genome homeostasis. Here we show that the conserved TRIM-NHL protein, NHL-2, plays an essential role in the C. elegans germline, modulating germline chromatin and meiotic chromosome organization. We uncover a role for NHL-2 as a co-factor in both positively (CSR-1) and negatively (HRDE-1) acting germline 22G-small RNA pathways and the somatic nuclear RNAi pathway. Furthermore, we demonstrate that NHL-2 ...


Resistance From Afar: Distal Mutation V36m Allosterically Modulates The Active Site To Accentuate Drug Resistance In Hcv Ns3/4a Protease, Aysegul Ozen, Kuan-Hung Lin, Keith P. Romano, Davide Tavella, Alicia Newton, Christos J. Petropoulos, Wei Huang, Cihan Aydin, Celia A. Schiffer 2018 University of Massachusetts Medical School

Resistance From Afar: Distal Mutation V36m Allosterically Modulates The Active Site To Accentuate Drug Resistance In Hcv Ns3/4a Protease, Aysegul Ozen, Kuan-Hung Lin, Keith P. Romano, Davide Tavella, Alicia Newton, Christos J. Petropoulos, Wei Huang, Cihan Aydin, Celia A. Schiffer

University of Massachusetts Medical School Faculty Publications

Hepatitis C virus rapidly evolves, conferring resistance to direct acting antivirals. While resistance via active site mutations in the viral NS3/4A protease has been well characterized, the mechanism for resistance of non-active site mutations is unclear. R155K and V36M often co-evolve and while R155K alters the electrostatic network at the binding site, V36M is more than 13 Angstrom away. In this study the mechanism by which V36M confers resistance, in the context of R155K, is elucidated with drug susceptibility assays, crystal structures, and molecular dynamics (MD) simulations for three protease inhibitors: telaprevir, boceprevir and danoprevir. The R155K and R155K ...


The Caenorhabditis Elegans Oxidative Stress Response Requires The Nhr-49 Transcription Factor, Queenie Hu, Dayana R. D'Amora, Lesley T. MacNeil, Albertha J. M. Walhout, Terrance J. Kubiseski 2018 York University

The Caenorhabditis Elegans Oxidative Stress Response Requires The Nhr-49 Transcription Factor, Queenie Hu, Dayana R. D'Amora, Lesley T. Macneil, Albertha J. M. Walhout, Terrance J. Kubiseski

Open Access Articles

The overproduction of reactive oxygen species (ROS) in cells can lead to the development of diseases associated with aging. We have previously shown that C. elegans BRAP-2 (Brca1 associated binding protein 2) regulates phase II detoxification genes such as gst-4, by increasing SKN-1 activity. Previously, a transcription factor (TF) RNAi screen was conducted to identify potential activators that are required to induce gst-4 expression in brap-2(ok1492) mutants. The lipid metabolism regulator NHR-49/HNF4 was among 18 TFs identified. Here, we show that knockdown of nhr-49 suppresses the activation of gst-4 caused by brap-2 inactivation and that gain-of-function alleles of ...


Conserved Mrna-Granule Component Scd6 Targets Dhh1 To Repress Translation Initiation And Activates Dcp2-Mediated Mrna Decay In Vivo, Quira Zeidan, Feng He, Fan Zhang, Hongen Zhang, Allan Jacobson, Alan G. Hinnebusch 2018 Eunice Kennedy Shriver National Institute of Child Health and Development

Conserved Mrna-Granule Component Scd6 Targets Dhh1 To Repress Translation Initiation And Activates Dcp2-Mediated Mrna Decay In Vivo, Quira Zeidan, Feng He, Fan Zhang, Hongen Zhang, Allan Jacobson, Alan G. Hinnebusch

Open Access Articles

Scd6 protein family members are evolutionarily conserved components of translationally silent mRNA granules. Yeast Scd6 interacts with Dcp2 and Dhh1, respectively a subunit and a regulator of the mRNA decapping enzyme, and also associates with translation initiation factor eIF4G to inhibit translation in cell extracts. However, the role of Scd6 in mRNA turnover and translational repression in vivo is unclear. We demonstrate that tethering Scd6 to a GFP reporter mRNA reduces mRNA abundance via Dcp2 and suppresses reporter mRNA translation via Dhh1. Thus, in a dcp2Delta mutant, tethered Scd6 reduces GFP protein expression with little effect on mRNA abundance, whereas ...


Trisomy Silencing By Xist Normalizes Down Syndrome Cell Pathogenesis Demonstrated For Hematopoietic Defects In Vitro, Jen-Chieh Chiang, Jun Jiang, Peter E. Newburger, Jeanne B. Lawrence 2018 University of Massachusetts Medical School

Trisomy Silencing By Xist Normalizes Down Syndrome Cell Pathogenesis Demonstrated For Hematopoietic Defects In Vitro, Jen-Chieh Chiang, Jun Jiang, Peter E. Newburger, Jeanne B. Lawrence

Open Access Articles

We previously demonstrated that an integrated XIST transgene can broadly repress one chromosome 21 in Down syndrome (DS) pluripotent cells. Here we address whether trisomy-silencing can normalize cell function and development sufficiently to correct cell pathogenesis, tested in an in vitro model of human fetal hematopoiesis, for which DS cellular phenotypes are best known. XIST induction in four transgenic clones reproducibly corrected over-production of megakaryocytes and erythrocytes, key to DS myeloproliferative disorder and leukemia. A contrasting increase in neural stem and iPS cells shows cell-type specificity, supporting this approach successfully rebalances the hematopoietic developmental program. Given this, we next used ...


Two Contrasting Classes Of Nucleolus-Associated Domains In Mouse Fibroblast Heterochromatin, Anastassiia Vertii, Jianhong Ou, Jun Yu, Aimin Yan, Hervé Pagès, Haibo Liu, Lihua Julie Zhu, Paul D. Kaufman 2018 University of Massachusetts Medical School

Two Contrasting Classes Of Nucleolus-Associated Domains In Mouse Fibroblast Heterochromatin, Anastassiia Vertii, Jianhong Ou, Jun Yu, Aimin Yan, Hervé Pagès, Haibo Liu, Lihua Julie Zhu, Paul D. Kaufman

University of Massachusetts Medical School Faculty Publications

In interphase eukaryotic cells, almost all heterochromatin is located adjacent to the nucleolus or to the nuclear lamina, thus defining Nucleolus Associated Domains (NADs) and Lamina Associated Domains (LADs), respectively. Here, we determined the first genome-scale map of murine NADs in mouse embryonic fibroblasts (MEFs) via deep sequencing of chromatin associated with purified nucleoli. We developed a Bioconductor package called NADfinder and demonstrated that it identifies NADs more accurately than other peak-calling tools, due to its critical feature of chromosome-level local baseline correction. We detected two distinct classes of NADs. Type I NADs associate frequently with both the nucleolar periphery ...


Stress-Responsive And Metabolic Gene Regulation Are Altered In Low S-Adenosylmethionine, Wei Ding, Daniel P. Higgins, Dilip K. Yadav, Adwait A. Godbole, Read Pukkila-Worley, Amy K. Walker 2018 University of Massachusetts Medical School

Stress-Responsive And Metabolic Gene Regulation Are Altered In Low S-Adenosylmethionine, Wei Ding, Daniel P. Higgins, Dilip K. Yadav, Adwait A. Godbole, Read Pukkila-Worley, Amy K. Walker

Open Access Articles

S-adenosylmethionine (SAM) is a donor which provides the methyl groups for histone or nucleic acid modification and phosphatidylcholine production. SAM is hypothesized to link metabolism and chromatin modification, however, its role in acute gene regulation is poorly understood. We recently found that Caenorhabditis elegans with reduced SAM had deficiencies in H3K4 trimethylation (H3K4me3) at pathogen-response genes, decreasing their expression and limiting pathogen resistance. We hypothesized that SAM may be generally required for stress-responsive transcription. Here, using genetic assays, we show that transcriptional responses to bacterial or xenotoxic stress fail in C. elegans with low SAM, but that expression of heat ...


Genome-Wide Crispr Screens For Shiga Toxins And Ricin Reveal Golgi Proteins Critical For Glycosylation, Songhai Tian, Khaja Muneeruddin, Mei Yuk Choi, Liang Tao, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Sebastian Boland, Scott A. Shaffer, Rosalyn M. Adam, Min Dong 2018 Harvard Medical School

Genome-Wide Crispr Screens For Shiga Toxins And Ricin Reveal Golgi Proteins Critical For Glycosylation, Songhai Tian, Khaja Muneeruddin, Mei Yuk Choi, Liang Tao, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Sebastian Boland, Scott A. Shaffer, Rosalyn M. Adam, Min Dong

Open Access Articles

Glycosylation is a fundamental modification of proteins and membrane lipids. Toxins that utilize glycans as their receptors have served as powerful tools to identify key players in glycosylation processes. Here, we carried out Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9-mediated genome-wide loss-of-function screens using two related bacterial toxins, Shiga-like toxins (Stxs) 1 and 2, which use a specific glycolipid, globotriaosylceramide (Gb3), as receptors, and the plant toxin ricin, which recognizes a broad range of glycans. The Stxs screens identified major glycosyltransferases (GTs) and transporters involved in Gb3 biosynthesis, while the ricin screen identified GTs and transporters involved in N-linked ...


Cryptococcus Neoformans Cda1 And Its Chitin Deacetylase Activity Are Required For Fungal Pathogenesis, Rajendra Upadhya, Lorina G. Baker, Woei C. Lam, Charles A. Specht, Maureen J. Donlin, Jennifer K. Lodge 2018 Washington University

Cryptococcus Neoformans Cda1 And Its Chitin Deacetylase Activity Are Required For Fungal Pathogenesis, Rajendra Upadhya, Lorina G. Baker, Woei C. Lam, Charles A. Specht, Maureen J. Donlin, Jennifer K. Lodge

Open Access Articles

Chitin is an essential component of the cell wall of Cryptococcus neoformans conferring structural rigidity and integrity under diverse environmental conditions. Chitin deacetylase genes encode the enyzmes (chitin deacetylases [Cdas]) that deacetylate chitin, converting it to chitosan. The functional role of chitosan in the fungal cell wall is not well defined, but it is an important virulence determinant of C. neoformans Mutant strains deficient in chitosan are completely avirulent in a mouse pulmonary infection model. C. neoformans carries genes that encode three Cdas (Cda1, Cda2, and Cda3) that appear to be functionally redundant in cells grown under vegetative conditions. Here ...


Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward, Ashley L. Cooney, Paul B. McCray, Patrick L. Sinn 2018 University of Iowa

Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward, Ashley L. Cooney, Paul B. Mccray, Patrick L. Sinn

Stead Family Department of Pediatrics Publications

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-regulated anion channel. Although CF is a multi-organ system disease, most people with CF die of progressive lung disease that begins early in childhood and is characterized by chronic bacterial infection and inflammation. Nearly 90% of people with CF have at least one copy of the ΔF508 mutation, but there are hundreds of CFTR mutations that result in a range of disease severities. A CFTR gene replacement approach would be efficacious regardless of the disease-causing mutation. After ...


Genetic Models Reveal Cis And Trans Immune-Regulatory Activities For Lincrna-Cox2, Roland Elling, Zhaozhao Jiang, Shiuli Agarwal, Mona Motwani, Jennie Chan, Shrutie Sharma, Katherine A. Fitzgerald, Susan Carpenter 2018 University of Massachusetts Medical School

Genetic Models Reveal Cis And Trans Immune-Regulatory Activities For Lincrna-Cox2, Roland Elling, Zhaozhao Jiang, Shiuli Agarwal, Mona Motwani, Jennie Chan, Shrutie Sharma, Katherine A. Fitzgerald, Susan Carpenter

Open Access Articles

An inducible gene expression program is a hallmark of the host inflammatory response. Recently, long intergenic non-coding RNAs (lincRNAs) have been shown to regulate the magnitude, duration, and resolution of these responses. Among these is lincRNA-Cox2, a dynamically regulated gene that broadly controls immune gene expression. To evaluate the in vivo functions of this lincRNA, we characterized multiple models of lincRNA-Cox2-deficient mice. LincRNA-Cox2-deficient macrophages and murine tissues had altered expression of inflammatory genes. Transcriptomic studies from various tissues revealed that deletion of the lincRNA-Cox2 locus also strongly impaired the basal and inducible expression of the neighboring gene prostaglandin-endoperoxide synthase (Ptgs2 ...


Understanding And Repurposing Crispr-Mediated Alternative Splicing, Jordan L. Smith, Haiwei Mou, Wen Xue 2018 University of Massachusetts Medical School

Understanding And Repurposing Crispr-Mediated Alternative Splicing, Jordan L. Smith, Haiwei Mou, Wen Xue

Open Access Articles

Two new studies refine our understanding of CRISPR-associated exon skipping and redefine its utility in engineering alternative splicing.


Robust Genome Editing With Short Single-Stranded And Long, Partially Single-Stranded Dna Donors In Caenorhabditis Elegans, Gregoriy A. Dokshin, Krishna S. Ghanta, Katherine M. Piscopo, Craig C. Mello 2018 University of Massachusetts Medical School

Robust Genome Editing With Short Single-Stranded And Long, Partially Single-Stranded Dna Donors In Caenorhabditis Elegans, Gregoriy A. Dokshin, Krishna S. Ghanta, Katherine M. Piscopo, Craig C. Mello

Open Access Articles

CRISPR-based genome editing using ribonucleoprotein complexes and synthetic single-stranded oligodeoxynucleotide (ssODN) donors can be highly effective. However, reproducibility can vary, and precise, targeted integration of longer constructs-such as green fluorescent protein tags remains challenging in many systems. Here, we describe a streamlined and optimized editing protocol for the nematode Caenorhabditis elegans We demonstrate its efficacy, flexibility, and cost-effectiveness by affinity-tagging 14 Argonaute proteins in C. elegans using ssODN donors. In addition, we describe a novel PCR-based, partially single-stranded, "hybrid" donor design that yields high efficiency editing with large (kilobase-scale) constructs. We use these hybrid donors to introduce fluorescent protein tags ...


Microtubule Acetylation Is Required For Mechanosensation In Drosophila, Connie Yan, Fei Wang, Yang Xiang, Stephen L. Rogers, Jay Z. Parrish 2018 University of Washington

Microtubule Acetylation Is Required For Mechanosensation In Drosophila, Connie Yan, Fei Wang, Yang Xiang, Stephen L. Rogers, Jay Z. Parrish

Open Access Articles

At the cellular level, alpha-tubulin acetylation alters the structure of microtubules to render them mechanically resistant to compressive forces. How this biochemical property of microtubule acetylation relates to mechanosensation remains unknown, although prior studies have shown that microtubule acetylation influences touch perception. Here, we identify the major Drosophila alpha-tubulin acetylase (dTAT) and show that it plays key roles in several forms of mechanosensation. dTAT is highly expressed in the larval peripheral nervous system (PNS), but it is largely dispensable for neuronal morphogenesis. Mutation of the acetylase gene or the K40 acetylation site in alpha-tubulin impairs mechanical sensitivity in sensory neurons ...


Rare Gene Fusion Rearrangement Sptnb1-Pdgfrb In An Atypical Myeloproliferative Neoplasm, Vanessa Fiorini Furtado, Neeraj Y. Saini, William V. Walsh, Venu G. Bathini, Patricia M. Miron 2018 University of Massachusetts Medical School

Rare Gene Fusion Rearrangement Sptnb1-Pdgfrb In An Atypical Myeloproliferative Neoplasm, Vanessa Fiorini Furtado, Neeraj Y. Saini, William V. Walsh, Venu G. Bathini, Patricia M. Miron

Open Access Articles

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia recognizes a distinct class of myeloid and lymphoid tumors with eosinophilia-related proliferations associated with specific gene rearrangements, one of which involves rearrangements of platelet-derived growth factor receptor B (PDGFRB) gene. We report a case of a rare PDGFRB rearrangement with SPTNB1 (spectrin beta, nonerythrocytic 1) that presented as atypical myeloproliferative neoplasm.


Fxr And Tgr5 Agonists Ameliorate Liver Injury, Steatosis, And Inflammation After Binge Or Prolonged Alcohol Feeding In Mice, Arvin Iracheta-Vellve, Charles D. Calenda, Jan Petrasek, Aditya Ambade, Karen Kodys, Luciano Adorini, Gyongyi Szabo 2018 University of Massachusetts Medical School

Fxr And Tgr5 Agonists Ameliorate Liver Injury, Steatosis, And Inflammation After Binge Or Prolonged Alcohol Feeding In Mice, Arvin Iracheta-Vellve, Charles D. Calenda, Jan Petrasek, Aditya Ambade, Karen Kodys, Luciano Adorini, Gyongyi Szabo

Open Access Articles

Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation plays a major role. OCA, INT-777, and INT-767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively. These compounds were tested in ...


Tip55, A Splice Isoform Of The Kat5 Acetyltransferase, Is Essential For Developmental Gene Regulation And Organogenesis, Diwash Acharya, Bernadette Nera, Zachary J. Milstone, Lauren Bourke, Yeonsoo Yoon, Jaime A. Rivera-Pérez, Chinmay M. Trivedi, Thomas G. Fazzio 2018 University of Massachusetts Medical School

Tip55, A Splice Isoform Of The Kat5 Acetyltransferase, Is Essential For Developmental Gene Regulation And Organogenesis, Diwash Acharya, Bernadette Nera, Zachary J. Milstone, Lauren Bourke, Yeonsoo Yoon, Jaime A. Rivera-Pérez, Chinmay M. Trivedi, Thomas G. Fazzio

Open Access Articles

Regulation of chromatin structure is critical for cell type-specific gene expression. Many chromatin regulatory complexes exist in several different forms, due to alternative splicing and differential incorporation of accessory subunits. However, in vivo studies often utilize mutations that eliminate multiple forms of complexes, preventing assessment of the specific roles of each. Here we examined the developmental roles of the TIP55 isoform of the KAT5 histone acetyltransferase. In contrast to the pre-implantation lethal phenotype of mice lacking all four Kat5 transcripts, mice specifically deficient for Tip55 die around embryonic day 11.5 (E11.5). Prior to developmental arrest, defects in heart ...


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